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1 2nd Department of Internal Medicine, Kochi Medical School, Nankoku, Kochi 783, Japan; and 2 Clinical Neuroendocrinology Branch, National Institute of Mental Health, Bethesda, Maryland 20892
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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In the rat, high-dose corticosterone (Cort) administration, the hypercortisolism of starvation, and adrenalectomy are all associated with decreased food intake and weight loss. We report here a study of the effects of high-dose Cort administration, starvation, and adrenalectomy on two peripheral hormones known to influence food intake and energy use, insulin and leptin. We also studied the impact of these interventions on the levels of type 2 corticotropin-releasing hormone receptor (CRHR-2) mRNA in the hypothalamic paraventricular nucleus (PVN) and ventromedial hypothalamus (VMH). The VMH is classically referred to as the satiety center because electrical stimulation of the VMH leads to inhibition of food intake, whereas CRHR-2 are thought to transduce the profound anorexogenic effects of CRH or its related peptide urocortin. Starvation and adrenalectomy each lowered plasma insulin and leptin levels and were associated with decrements in CRHR-2 mRNA levels in the VMH. Cort administration increased plasma leptin levels profoundly, as well as plasma insulin levels and the levels of VMH CRHR-2 mRNA. Under all experimental conditions, a positive correlation was seen between plasma leptin levels and VMH CRHR-2 mRNA. These data suggest that decreased food intake and weight loss after high-dose Cort administration at least partially depend on the profound impact of Cort on plasma leptin secretion in the rat; they suggest, moreover, an additional mechanism for the satiety-inducing effects of leptin, namely increasing CRHR-2 in the VMH. The concordance of a fall in plasma insulin and leptin levels with the fall in VMH CRHR-2 mRNA levels further supports the idea that compensatory responses during starvation and adrenalectomy include not only the disinhibiting effects of reduced insulin and leptin levels on appetite through already-described mechanisms but also via an effect of leptin on VMH CRHR-2. Neither Cort administration, starvation, nor adrenalectomy influenced the levels of CRHR-2 mRNA in the PVN, suggesting that these receptors are differentially regulated in different hypothalamic regions.
corticotropin-releasing hormone; ventromedial hypothalamus; insulin; leptin
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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THE ADMINISTRATION OF high doses of corticosterone (Cort), starvation, and adrenalectomy are all associated with weight loss. However, these three experimental conditions do not result in uniform changes in appetite. Thus weight losses secondary to high Cort administration and adrenalectomy are both associated with anorexia, whereas starvation is associated with marked increases in appetite (4, 5, 28). The availability of three experimental models all producing weight loss yet having differing effects on appetite regulation allows for an examination of the relationship between new peripheral and central nervous system hormones and receptors that regulate appetite without the confounding variable of disparities in the loss or gain in weight. For example, recent research has led to the discovery of the adipocyte-derived hormone leptin as an important inhibitor of food intake (38) and the isolation and cloning of the type 2 corticotropin-releasing hormone receptor (CRHR-2) located in the hypothalamus and thought to mediate the anorexogenic effects of urocortin and/or CRH itself (13, 15, 23, 24, 34).
Although glucocorticoids and insulin are thought to play critical roles in energy homeostasis (4), the mechanisms by which these three interventions all lead to the same outcome have not been definitively elucidated. The discovery of new peripheral and central nervous system hormones and/or receptors such as leptin and CRHR-2 that each regulate appetite and energy use provides new means for exploring these questions. Moreover, understanding the interactions among plasma Cort, insulin, and leptin levels and central effectors such as the CRHR-2 under varying conditions may provide new insights into the mechanisms of the regulation of weight homeostasis. We report here a study of changes in CRHR-2 mRNA levels in the ventromedial hypothalamus (VMH) and hypothalamic paraventricular nucleus (PVN) in relationship to peripheral variables related to energy homeostasis under three conditions known to produce weight loss in the rat, namely Cort administration, adrenalectomy, and starvation. We asked the following questions. 1) Were there alterations in hypothalamic CRHR-2 mRNA levels in the weight loss occurring under any of these three experimental conditions? 2) If so, were these changes in hypothalamic CRHR-2 mRNA levels related to weight loss per se or to any components of the specific repertoire of physiological alterations that occurred (e.g., increased or decreased plasma Cort, insulin, leptin)? 3) Were changes in VMH or PVN CRHR-2 mRNA levels consistent or discordant under these experimental conditions?
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Male Wistar rats (Japan SLC, Hamamatsu, Japan) weighing 260-290 g, were housed at 24°C in a humidity-controlled room. They were maintained under a 12:12-h light-dark cycle (lights on at 0600 and off at 1800). Standard rat biscuits and water were available ad libitum throughout the experiments, except in experiment 4.
Experiment 1. Male Wistar rats were
randomly separated into three groups and injected
subcutaneously twice daily (0800-0900 and
1900-2000) with either vehicle (sesame oil) or Cort (low, 2 mg · rat
1 · day1;
high, 10 mg · rat1 · day1,
dissolved in sesame oil; Sigma Chemical, St. Louis, MO). Rats received
injections for 12 days (n = 8 in each
group) and were killed 12-13 h after the last injection.
Experiment 2. To confirm the effect of high-dose Cort administration, male Wistar rats were implanted with either a 200-mg Cort pellet (n = 7, 21-day release; Innovative Research of America, Sarasota, FL) or a placebo pellet (n = 5) under pentobarbital sodium anesthesia (42 mg/kg body wt ip; Nembutal, Abbott). Rats were killed at 7 or 14 days after implantation.
Experiment 3. Another set of male Wistar rats was used for the adrenalectomy study. They were bilaterally adrenalectomized (7 adrenalectomized and 7 sham) via a dorsal approach under pentobarbital sodium anesthesia. Isotonic saline (0.9%) was given after surgery in both adrenalectomized and sham rats. Rats were killed 7 days after surgery.
Experiment 4. Another set of male Wistar rats was randomly separated into three groups. Control rats had access to water and food ad libitum, and starved rats were given water only for 2 or 4 days (n = 8 in each group).
For all experiments, the rats were decapitated between 1000 and 1200, corresponding to 4-6 h after lights-on, and their brains were
quickly removed and frozen by immersion in 2-methyl butane at
30°C, then stored at 70°C until sectioning of the
tissue on the cryostat. The trunk blood was also collected on ice at the time of decapitation, centrifuged, and stored at 70°C
until assay. Plasma Cort, insulin, and leptin were measured by
commercially available kit (Cort: radioimmunoassay kit, ICN
Biomedicals, Cleveland, OH; insulin: ELISA kit, Morinaga Biochemical,
Yokohama, Japan; leptin: radioimmunoassay kit, Linco Research, St.
Charles, MO). Plasma glucose was measured with Glutest EII system
(Sanwa Chemical, Nagoya, Japan). The intra-assay and interassay
coefficients of variance were <10%.
In situ hybridization. Frozen tissue
was cut coronally in 15-µm-thick sections for in situ hybridization
histochemistry in the VMH and the PVN. The sections were taken from the
following sites: VMH, 2.70-3.20 mm, and PVN, 1.60-1.90 mm
posterior from the bregma. The sections were thaw-mounted and air dried
on gelatin-coated slides and were stored at 70°C before in
situ hybridization histochemistry.
CRHR-2 cRNA probe was generously given to us by Drs. T. W. Lovenberg and E. B. De Souza. The pBluescript contains a 460-bp corresponding to the 5' region of CRHR-2, covering the sequence up to the third presumed transmembrane region (2). The template was
linearized, and then antisense probe labeled with
[
-35S]UTP (DuPont
NEN, Wilmington, DE) was generated by transcription of the linearized
plasmid DNA with the use of the Riboprobe System (Promega Biotech,
Madison, WI). We modified the standard Promega labeling method and
increased the concentration of
[-35S]UTP from 62.5 to 187.5 µCi for 1 µg of linearized DNA labeling. This improved the
sensitivity for detecting CRHR-2 mRNA. The cRNA probe was purified by
extraction with Nuctrap push columns (Stratagene, La Jolla, CA).
We used the hybridization procedures described previously (18). In brief, sections were fixed in 4% formaldehyde and subsequently treated with 0.25% acetic anhydride in 0.1 M triethanolamine-0.9% saline (pH 8.0) over a 10-min period to reduce nonspecific hybridization of the probe. Then the sections were dehydrated in increasing concentrations of ethanol and delipidated with chloroform for 5 min, rinsed in ethanol, and air dried. For oligonucleotide probes, sections were hybridized overnight at 37°C with 5 × 105 counts/min (cpm) of labeled NPY probe per section, then washed four times (15 min each) with 2× SSC (1× = 0.15 M NaCl-0.015 M sodium citrate, pH 7.2) containing 50% formamide at 40°C, followed by two 30-min rinses with 1× SSC at 25°C. For riboprobes, sections were hybridized overnight at 54°C with 5 × 105 cpm of labeled probe per section. Then the nonspecifically hybridized probe was removed through washing procedures as follows. The sections were rinsed with 4× SSC for 5 min on four separate occasions. They were incubated with the RNase A (Boehringer-Mannheim Biochemicals, Indianapolis, IN; 20 µg/ml in RNase buffer) solution at room temperature for 30 min, followed by wash with 0.1× SSC-0.1 mM 1,4-dithiothreitol solution at 65°C for 60 min. Finally, the slides were dehydrated for 1 min in ascending alcohols (50, 70, 90, and 95% ethanol containing 300 mM ammonium acetate and 100% ethanol).
Analysis and quantification. For
analysis of CRHR-2 mRNA, the slides and
14C-labeling standards of known
radioactivity (American Radiochemicals, St. Louis, MO) were placed in
X-ray cassettes, apposed to
35S-sensitive film
(Hyperfilm-
Max, Amersham) for the following durations: 8 days for
CRHR-2 in the VMH and 21 days for CRHR-2 in the PVN. Films were then
developed (Rendol, Fuji Photo, Tokyo, Japan) for 5 min at 20°C. To
determine the anatomic localization of probe at the cellular level in
the VMH, sections were dipped in NR-M2 autoradiographic emulsion
(Konica, Tokyo, Japan), exposed for 4-5 wk, developed (Rendol,
Fuji) for 2 min at 16°C, and counterstained with thionine. The
amounts of probe hybridized in the VMH were measured as regional
optical densities of autoradiographic film images with a computerized
image analysis system composed of a light box, a solid-state video
camera, and Macintosh II-based IMAGE software developed by Wayne
Rasband, Research Service Branch, National Institute of Mental Health.
Optical densities for each region were obtained in six sections per rat
in the VMH and in two consecutive sections per rat in the PVN. Values
were converted to disintegrations per minute per milligram (dpm/mg) of
rat brain tissue using a standard curve generated by
14C standards that had been
matched with
[-35S]dATP-impregnated
rat brain paste standards. The average value for each rat was used to
calculate group means. Statistical significance between the control and
experimental groups was determined by ANOVA in
experiments
1, 2,
and 4, followed by
Student-Newman-Keuls test. In
experiment
3, results were analyzed by the
unpaired Student's t-test.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Experiment 1: Effects of systemic Cort injection. Table 1 shows the changes in body weight, food intake, and peripheral hormonal values during Cort injection. Compared with vehicle-treated rats, Cort-injected rats lost their body weight in a dose-dependent manner (2 mg, P < 0.05; 10 mg, P < 0.01), and Cort injection, either low (2 mg/day) or high (10 mg/day), had a similar inhibitory effect on food intake (P < 0.01).
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Rats with subcutaneous injection of Cort (10 mg/day) had higher levels of plasma Cort than vehicle-treated and 2 mg Cort-injected rats (P < 0.01). Plasma glucose levels were significantly lower, whereas plasma insulin and leptin levels were significantly higher, in 10 mg Cort-injected group than vehicle-treated and 2 mg Cort-injected rats (P < 0.01).
Figures 1 and 2 present the effects of Cort injection on the changes in CRHR-2 mRNA in the VMH. CRHR-2 mRNA in the VMH significantly increased after high Cort injection (P < 0.01), whereas CRHR-2 mRNA level in the PVN was not altered (Fig. 2).
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Experiment 2: Effects of Cort pellet implant. An implant of a 200 mg Cort pellet produced a comparable level of plasma Cort at 7 and 14 days compared with the levels by high Cort (10 mg/day) administration in experiment 1 (P < 0.01 vs. vehicle; Table 1). Similar to the effects of high Cort administration, Cort pellet implantation reduced body weight and food intake at both 7 and 14 days. Plasma insulin and leptin levels were increased at both 7 and 14 days (P < 0.01), the effects homologous to those of high Cort administration.
Similar to Cort injection, CRHR-2 mRNA in the VMH, not in the PVN, significantly increased after Cort pellet implantation for both 7 and 14 days (P < 0.01; Fig. 3). Thus Cort pellet implantation reproduced the effects of high Cort administration on the peripheral and central variables that we measured.
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Experiment 3: Effects of adrenalectomy. Plasma Cort levels in adrenalectomized rats were below the detectable limit (Table 1). In contrast to the effects of high Cort, both plasma insulin and leptin levels were decreased after adrenalectomy (insulin P < 0.05; leptin P < 0.01). Regardless of the opposite effects on the above-mentioned variables compared with those of high Cort, adrenalectomized rats also decreased their weights and food intake.
Figures 1 and 4 show the opposite changes in CRHR-2 mRNA in the VMH 7 days after adrenalectomy, compared with those of high Cort administration observed in experiments 1 and 2. CRHR-2 mRNA in the VMH was reduced after adrenalectomy (P < 0.05 vs. sham rats). Similar to the high Cort administration, CRHR-2 mRNA in the PVN was not altered after adrenalectomy (Fig. 4).
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Experiment 4: Effects of starvation. Table 2 shows the changes in body weight and peripheral hormonal values during starvation. Plasma Cort increased (P < 0.01) during four days of starvation. Plasma glucose, insulin, and leptin levels were all decreased along with decreased body weight.
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Figures 5 and 6 present the effects of starvation on the changes in CRHR-2 mRNA in the VMH. CRHR-2 mRNA in the VMH showed a slight but significant decrease at 4 days of starvation (P < 0.01). Thus the effects of starvation on the VMH CRHR-2 mRNA level were opposite to those of high Cort. CRHR-2 mRNA in the PVN, however, was not altered (Fig. 5).
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Correlations between plasma leptin or insulin levels and VMH CRHR-2 mRNA. Throughout the present study, alterations in plasma insulin and leptin appeared to be proportionate to the changes in VMH CRHR-2 mRNA. We conducted the regression analysis to evaluate whether there were correlations between plasma insulin or leptin levels and VMH CRHR-2 mRNA. Figure 7 shows a scattered plot for individual rats in all experiments. The positive correlation was seen between plasma leptin and VMH CRHR-2 (r = 0.232, P < 0.05) but not between plasma insulin and VMH CRHR-2 (r = 0.116).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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We report here changes in hypothalamic CRHR-2 mRNA levels and peripheral variables related to the energy homeostasis after Cort administration, adrenalectomy, and starvation. High Cort reduced food intake and body weight, increased plasma insulin and leptin levels, and increased levels of VMH CRHR-2 mRNA. Although reductions in food intake and weight also occurred with adrenalectomy, the opposite changes occurred (i.e., decreased plasma insulin and leptin levels and decreased VMH CRHR-2 mRNA levels). Despite increased plasma Cort levels, starvation resulted in changes similar to those seen during adrenalectomy: decreased plasma insulin and leptin levels and decreased VMH CRHR-2 mRNA levels. There was a positive correlation in all cases between plasma leptin levels and CRHR-2 mRNA levels. In contrast, PVN CRHR-2 mRNA levels were unaltered by any of these interventions.
Our data are in agreement with previous studies regarding the impact of high-dose Cort administration, adrenalectomy, and starvation on weight, food intake, and plasma insulin and leptin concentrations (1, 4, 7, 22, 28, 30). On the other hand, alterations of CRHR-2 mRNA in brain under different experimental conditions has not been previously demonstrated. Thus 60 min of treadmill running failed to affect VMH CRHR-2 mRNA levels in lean and obese Zucker rats (26). To our knowledge, the present study is the first report showing changes in VMH CRHR-2 mRNA levels under in vivo conditions.
At first glance, the findings that Cort administration increased and adrenalectomy decreased VMH CRHR-2 mRNA suggests regulation of VMH CRHR-2 mRNA by circulating glucocorticoids. During the hypercortisolism of starvation, however, decreased VMH CRHR-2 mRNA levels were observed, indicating that Cort levels are not systematically related to VMH CRHR-2 mRNA levels. On the other hand, changes in CRHR-2 mRNA levels in VMH appeared to be proportionate to the changes in both plasma insulin and plasma leptin levels. Consequently, however, regression analysis revealed that a positive correlation was observed between plasma leptin levels and VMH CRHR-2 mRNA but not between plasma insulin and VMH CRHR-2 mRNA. Thus the change in VMH CRHR-2 mRNA is more closely linked to changes in plasma leptin levels than to plasma insulin or Cort levels. The anatomic context for these effects has been established by the demonstration of leptin receptor mRNA (21) in the arcuate nucleus and VMH, where the blood-brain barrier is relatively permeable. In this context, it is of great interest that Richard et al. (26) demonstrated strain differences between lean and obese Zucker in VMH CRHR-2 mRNA levels, with obese rats showing lower levels of VMH CRHR-2 mRNA than lean rats. Low CRHR-2 mRNA in obese Zucker rat may be attributable to the loss of leptin effect due to leptin receptor mutation (3).
In rats, both CRH and a novel CRH-related peptide, urocortin, could be endogenous ligands for CRH receptors (37). It has been reported that type 1 CRH receptor (CRHR-1) mRNA is regulated by CRH in a site-specific manner (11, 20, 25); yet the regulation of CRHR-2 mRNA by CRH or urocortin is uncertain. Anatomically, it is not likely that VMH CRHR-2 mRNA is regulated by local CRH, because CRH-containing neurons and their terminals are sparse in the region of the VMH (36). However, urocortin-containing nerve terminals are evident in the VMH, although their origin is unknown (Dr. W. Vale, personal communication). This anatomic evidence and the previous finding that the anorexogenic effect of the central injection of urocortin, which has a higher affinity for CRHR-2 than CRH (37), is more potent than that of CRH (31) may suggest urocortin as a more possible ligand for VMH CRHR-2 than CRH. Alterations of urocortin concentrations in the VMH and their possible contribution to the regulation of VMH CRHR-2 mRNA levels remain to be clarified.
CRHR-2 activation of the VMH would be expected to diminish food intake, based both on the classical finding that electrical stimulation of the VMH reduces food intake (33) and the demonstration of the anorexogenic effects of urocortin administration (31). During starvation, a decrease in VMH CRHR-2 mRNA is presumably associated with the decreased VMH activity, which would enhance the counterregulatory feeding response to starvation. In contrast, reduced food intake observed during the course of high Cort administration may be attributable at least partially to the activation of VMH neurons via CRHR-2. Our finding of the positive correlation between plasma leptin concentrations and levels of CRHR-2 mRNA in the VMH suggests an additional mechanism for the anorexogenic effects of leptin, namely that of increasing VMH CRHR-2 mRNA levels and signal transduction. It has been previously shown that the injection of leptin into the VMH results in decreased food intake in the rat (12), whereas Elmquist et al. (8) found that systemic administration of leptin activated the VMH as detected by Fos-like immunoreactivity.
In this context, however, it should be noted that adrenalectomy decreased food intake despite decreased VMH CRHR-2 mRNA levels. We cannot definitely account for this observation, but it could relate to the profound disinhibition of PVN CRH expected in the context of glucocorticoid insufficiency or in the loss of glucocorticoid-mediated neuropeptide Y release (29). Whether decreased VMH CRHR-2 mRNA in the course of adrenalectomy was a compensatory response remains to be clarified.
Previous data showed that low to moderate doses of glucocorticoids stimulate food intake, but, at high dose, glucocorticoid-induced insulin secretion, at least in part, reduces or even overrides the stimulation of feeding by glucocorticoids (4-6, 35). Although we cannot eliminate the possibility that Cort per se stimulated food intake, the present results suggest that, in addition to insulin, Cort-mediated leptin secretion may also mask the stimulatory effect of glucocorticoid on food intake after high dose of Cort administration.
Previous work has shown that injection of CRH directly into the VMH also increases sympathetic nervous system activity (9), analogous to the effects of electrical stimulation of the VMH (32). Because sympathetic nervous system activation produces brown adipose tissue (BAT) thermogenesis (10), CRH could act as a catabolic neuropeptide in the VMH via CRHR-2 to facilitate energy expenditure through BAT thermogenesis. This idea is supported by the previous data of Richard et al. (26) showing that low VMH CRHR-2 in obese Zucker rats presumably contributes to the development of obesity via both decreased food intake and decreased energy use. These putative functions of VMH CRHR-2 suggest that high-dose Cort administration reduces food intake and reduces weight, in part, via plasma leptin-mediated increases in VMH CRHR-2 mRNA levels, and that the reduction of VMH CRHR-2 mRNA levels during starvation and adrenalectomy may promote survival by promoting increased food intake and more efficient energy use.
In contrast to the impact of exogenous hypercortisolism in the rat to raise plasma leptin levels and the levels of VMH CRHR-2 mRNA, starvation reduced each of these parameters despite the hypercortisolism. The likely explanation for this disparity is that during exogenous Cort administration, food was provided for substrate to elevate plasma leptin levels, which, in turn, increased VMH CRHR-2 mRNA levels, leading to a decrease in the consumption of available food. No food was available during the course of the starvation study. Thus the loss of adipose tissue overrode the impact of hypercortisolism to increase leptin concentrations. In the light of the positive correlation between plasma leptin concentrations and VMH CRHR-2 mRNA levels, a concomitant decrease in plasma leptin concentrations in food-deprived rats was a likely contributor to the fall in VMH CRHR-2 mRNA levels. The fall in VMH CRHR-2 could promote survival during starvation by leading to both increased hunger and decreased BAT thermogenesis.
The unaltered PVN CRHR-2 mRNA levels during Cort administration, adrenalectomy, and starvation are consistent with previous reports directly investigating the effects of these interventions on PVN CRHR-2 mRNA levels (19) and the failure of direct CRH injection into the PVN to influence PVN CRHR-2 mRNA levels (20). On the other hand, we and others have previously shown that PVN CRHR-1 mRNA levels are significantly altered by Cort administration, adrenalectomy, and various stressful situations (16, 17, 19, 27). It should be noted, however, that the local injection of CRH into the PVN has been shown to be capable of inducing anorexia (14), so that unaltered PVN CRHR-2 mRNA levels during interventions such as starvation do not exclude its possible participation in the regulation of food intake and energy homeostasis. Whether PVN CRH acting locally or PVN CRHR-2s are of physiological significance with regard to the regulation of energy homeostasis remains to be clarified.
Perspectives
A complex array of molecules influences appetite regulation. Recently, the CRHR-2 has been cloned, and its binding with either urocortin or CRH results in a profound decrement in food intake in the rat. The present paper attempted to explore possible interactions between CRHR-2 mRNA levels with other, more established modulators of food intake, such as plasma leptin, plasma insulin, and plasma Cort. Hypothalamic CRHR-2 mRNA levels were studied under three experimental conditions that all resulted in weight loss (i.e., starvation, Cort administration, and adrenalectomy). Levels were measured in the VMH, known as the satiety center because electrical stimulation there leads to decreased food intake, and in the PVN, another hypothalamic area thought to be involved in appetite regulation.The only consistent relationship seen among the various modulators of food intake with VMH CRHR-2 mRNA levels was a significant positive correlation between plasma leptin levels and CRHR-2 mRNA levels in the VMH. These data suggest that the VMH CRHR-2 mediates appetite regulation, in part, as a target of peripheral leptin as well as via a receptor for urocortin (and possibly CRH). Conversely, these data strongly suggest another central target for leptin actions, namely CRHR-2.
The development of a selective agonist or antagonist of CRHR-2 will clarify the exact role of VMH CRHR-2. Furthermore, the exploration of the impact of leptin administration on CRH, urocortin, and VMH CRHR-2 in the VMH will result in the construction of an overview of leptin's effects on CRH systems in the central nervous system.
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ACKNOWLEDGEMENTS |
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The authors thank Drs. Timothy Lovenberg and Errol B. DeSouza (Neurocrine Biosciences, San Diego, CA) for providing us a plasmid containing rat CRHR-2 cDNA.
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FOOTNOTES |
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Address for reprint requests: S. Makino, 2nd Dept. of Internal Medicine, Kochi Medical School, Okoh-cho, Nankoku, Kochi 783, Japan.
Received 26 November 1997; accepted in final form 24 June 1998.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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